A greater understanding of phenotypic characteristics of, and of genetic influences on, nicotine withdrawal may help decrease morbidity and mortality in heavily dependent and relapsing smokers. The Candidate is applying for a Mentored Clinical Scientist Development Award (K08) in order to develop an independent line of research to address this serious problem. The PI has extensive experience in smoking cessation research and seeks to augment her training in statistical genetics and related quantitative methods, and assessment of tobacco use behaviors, and to increase her familiarity with molecular genetics procedures, and the neurobiology of nicotine. The goal of this research is to develop an improved assessment of nicotine withdrawal for genetic research, guided by findings from animal and previous human research, using interview and laboratory measures of negative affect, positive affect, and physical symptoms of withdrawal; and to apply this in a case-control study of genetic association. The first stage will be analysis of existing data, to determine the genetic structure of DSM-IV nicotine withdrawal symptoms, and the degree of overlap of genetic influences on nicotine withdrawal versus regular smoking, after control for other psychiatric and sociodemographic risk factors. Concurrently a small laboratory study (N=60) will address the validity and short-term reliability of factors derived from a more extensive battery of withdrawal symptoms. Guided by these results, an extensive follow-up assessment of nicotine withdrawal will be conducted in Australia of a target sample of 400 cases reporting withdrawal, and 400 controls (selection guided by first stage analyses), from whom DMAs and baseline DSM-IV interview data have already been obtained. The baseline assessment of nicotine withdrawal will be augmented by adding reliable and valid questions about decreases in positive as well as negative affect and physical symptoms. Three candidate genes (CHRNB2, OPRM1, CHRNA3) will be typed and tested for hypothesized differential associations with negative affect versus positive affect versus physical symptoms. The long-term goal of this research and training program is to prepare the applicant to establish an independent research career combining retrospective and contemporaneous assessments, both laboratory-based and interview, in pharmacogenetic research on smoking cessation failure and nicotine withdrawal.